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Acute Myeloid Leukemia
Pimjai Niparuck
Division of Hematology, Department of Medicine
Ramathibodi Hospital, Mahidol University
Outline
• Molecular biology
• Chemotherapy and Hypomethylating agent
• Novel Therapy
Treatment
Treatment for elderly patients with AML
A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,
A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,
Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (≥ 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III
Randomized Multicentre Study (EudraCT 2008-001290-15)
• 117 patients were randomly 1:1
1. observation (control group )
2. azacitidine maintenance (aza group), 50 mg/m2 (5 days) q 4 weeks, until relapse for a maximum of 12 cycles
• 52 patients received at least 1 cycle of aza
44, 40, 34 and 32 patients received at least 3, 6, 9 and 12 cycles respectively
• The 12 months DFS = 39% (control group), 63% (aza group)
Difference in OS between the two groups : not statistically significant in the cohort of patients in this pre-final analysis
• The 12 months OS (after censoring allo transplanted patients) = 64% (control group), 83% (aza group)
• Subgroup analysis (CR vs CRi at inclusion) revealed that patients with platelet count ≥ 100 x 109/L had a significant better OS in favor of aza maintenance treatment (logrank; p=0.01).
Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (≥ 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III
Randomized Multicentre Study (EudraCT 2008-001290-15)
Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics
• Adult pts with R/R AML or myelodysplastic syndromes (MDS) and preserved organ function
with a WBC<10,000/μL (hydroxyurea permitted) were eligible. The tx consisted of aza 75 mg/m2 d1-7, a bone marrow biopsy on cycle (C) 1 day 8, len 50 mg d8-28, and 2 weeks off tx, constituting a 42-day cycle.
Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics
Novel Therapy
Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years
• Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC)
• Total= 71 pts, median age, 74 years [range, 66-87 years]
• cycle 1, VEN 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28
• In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28
• LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle
Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years
Phase II Study: Frontline Cytarabine and Idarubicin + Nivolumab in Newly
Diagnosed AML
Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017,* December 9-12, Atlanta, Georgia *CCO is an independent medical education company that provides state-of-
the-art medical information to healthcare professionals through conference
coverage and other educational programs.
This activity is supported by educational grants from AbbVie; AstraZeneca;
Celgene Corporation; Genentech; Janssen Biotech, Inc administered by
Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals; Novartis
Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and
Takeda Oncology.
Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design
Pts 18-60 yrs of age
(or > 60 if very fit)
with either AML by WHO
criteria or high-risk MDS
with ≥ 10% blast cells;
ECOG PS 0-2;
adequate cardiac, renal,
hepatic function (N = 35)
Cytarabine 1.5 g/m² IV D1-4*
Idarubicin 12 mg /m² IV QD x 3
Nivolumab† 3 mg/kg Q2W starting on D24 ± 2 days
Induction
Ravandi F, et al. ASH 2017. Abstract 815. ClinicalTrials.gov. NCT02464657.
Cytarabine 0.75 g/m² IV QD x 3
Idarubicin 8 mg /m² IV QD x 3
≤ 5 cycles
Nivolumab 3 mg/kg Q2W
≤ 1 yr
Consolidation Maintenance
*Cytarabine given over 24 hours; pts older than 60 yrs of age received 3 days instead of 4. †First 3 pts treated at run-in phase with nivolumab 1 mg/kg with no drug-related toxicity. The remaining 32 pts treated as noted in schema.
Slide credit: clinicaloptions.com
Allogeneic SCT for eligible pts at any time during or after consolidation
• Primary endpoint: MTD of nivolumab (phase I)
• Secondary endpoint: EFS (phase I/II)
Characteristic IA + Nivolumab
(N = 35)
Median age, yrs (range) 54 (26-65)
Male, % 43
Median WBC x 109/L (range) 5 (0.4-46.1)
Median creatinine, mg/dL (range) 0.8 (0.51-1.31)
Median bilirubin, mg/dL (range) 0.7 (0.2-2.5)
Median BM blasts, % (range) 42 (15-96)
AML/MDS, %
De novo AML
Secondary AML
Therapy-related AML
High-risk MDS (≥ 10% blasts)
74
11
9
6
Previous therapy for MDS, %
None
Hypomethylating agents
89
11
Characteristic, % IA + Nivolumab (N =
35)
Cytogenetics
Diploid
Other
intermediate
-7/7q-/-
5/complex
23
23
40
ELN
Favorable
Intermediate
Adverse
14
46
40
Mutations
FLT3-ITD
FLT3-0835
NPM1
TP53
IDH1
IDH2
DNMT3A
KRAS/NRAS
9
9
17
23
6
23
17
14 Ravandi F, et al. ASH 2017. Abstract 815.
Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design
0 3 6 9 12
15
18
Ravandi F, et al. ASH 2017. Abstract 815.
OS Event-Free Survival
Relapse-Free
Survival
Median OS: 15.8 mos (range: 0.5-21.1) N = 35; 12 died
Median EFS: 8.3 mos (range: 0.5-18.0) N = 35; 17 events
Median RFS: 17.3 mos (range: 0.6-17.3) N = 26 (CR/CRi/CRp); 9 relapses
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Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design